Biocompatible polymeric materials are used for a number of medical applications. For example, biocompatible synthetic polymers such as expanded polytetrafluorethylene and polyethyleneterephthalate (e.g. DACRON) are used to construct vascular grafts. A wide variety of biodegradable polymers are combined with drugs and formed into microspheres and other structures to provide implantable devices for timed-release drug delivery. Biodegradable polymers are also used for sutures, surgical screws, plates and pins that are widely used in surgery, including orthopedic surgery.
Naturally occurring polymers, such as proteins, are also used medically. For example, fibrinogen-based tissue adhesives are used to control bleeding and to reattach or reconstruct severed or damaged tissue. These adhesives are used alone or in conjunction with mechanical fasteners such as sutures or staples. Although a number of fibrinogen-based tissue adhesives have been reported (see, for review, Sierra, J. Biomat. Appl. 7: 309-352, 1993), their use has been limited by the need to extract fibrinogen from plasma, which carries a risk of disease transmission, and by the problems related to the purity of the bovine thrombin used as the clotting catalyst in some of the current products. Bovine thrombin preparations are extremely impure, and are suspected of being immunogenic (Strickler et al., Blood 72: 1375-1380, 1988; Zehnder et al., Blood 76: 2011-2016, 1990; Lawson et al., Blood 76: 2249-2257, 1990). Antibodies elicited by the bovine thrombin preparations interact with human proteins and leave the patient's clotting system impaired. To date, the production of recombinant fibrinogen in commercial quantities has not been reported.
Elastomeric polypeptides have been disclosed, for example, in U.S. Pat. Nos. 4,500,700; 4,870,055; and 4,187,852. These patents disclose small synthetic polypeptides that may be polymerized to produce insoluble cross-linked elastomeric fibers or cellophanelike sheets. U.S. Pat. Nos. 4,132,746; 4,187,852; 4,870,055 and 4,589,882 disclose methods of producing randomly cross-linked elastomeric copolymers using enzymatic, chemical or .gamma.-radiation induced cross-linking. PCT publication WO 88/03533 discloses polyoligomers of repeating, relatively short, amino acid sequence units. The polyoligomers are produced by recombinant DNA methodology, and are exemplified by silk-like proteins. WO 90/05177 discloses similar polyoligomers wherein strands of repeating units capable of assembling into aligned structures are interspersed with unaligned oligopeptides. While these polymers provide structural matrices, they are not bioadhesive and are not suitable for in vivo use. While, as discussed above, methods of producing cross-linked polymers have been disclosed the methods may be inappropriate for in vivo use due to the toxicity of the cross-linking agent or the rate of cross-linking.
There remains a need in the art for biomaterials that can be polymerized into homo- and copolymers that are capable of forming stable matrices of aligned structures that are cross-linked in a chemically defined manner. There is a further need for matrices capable of adhering to animal tissue to facilitate surgical sealing, as well as subsequent wound healing and tissue restructuring. There is also a need for tissue adhesives that do not contain blood-derived components. There is an additional need for biomaterials whose physical properties can be altered by adjusting environmental parameters, such as pH, temperature, or ionic strength, allowing them to be formed in situ. The present invention provides such materials as well as other, related advantages.